non-anion gap metabolic acidosis (nagma)

Interesting Electrolyte Cases

Joel M. Topf, M.D.

Nephrology

248.470.8163

http://PBFluids.blogspot.com

58 y.o. female with weakness and muscle aches

139 115 3.1 17

16

1.0

7.34 / 87 / 33 / 17

Determine the primary acid-base disorder

1. Acidosis or alkalosis– If the pH is less than 7.4 it is acidosis– If the pH is greater than 7.4 it is alkalosis

2. Determine if it is respiratory or metabolic– If the pH, bicarbonate and pCO2 all move in the same

direction (up or down) it is metabolic

– If the pH, bicarbonate and pCO2 move in discordant directions (up and down) it is respiratory

7.34 / 87 / 33 / 16pH / pO2 / pCO2 / HCO3






7.34 / 87 / 33 / 16pH / pO2 / pCO2 / HCO3


7.34 / 87 / 33 / 16pH / pO2 / pCO2 / HCO3






7.34 / 87 / 33 / 16pH / pO2 / pCO2 / HCO3


7.34 / 87 / 33 / 16pH / pO2 / pCO2 / HCO3

2. Determine if it is respiratory or metabolic– If the pH, bicarbonate and pCO2 all move in the

same direction (up or down) it is metabolic


Determine the primary disorder





7.34 / 87 / 33 / 16pH / pO2 / pCO2 / HCO3


7.34 / 87 / 33 / 16pH / pO2 / pCO2 / HCO3




Metabolic Acidosis

Predicting pCO2 in metabolic acidosis: Winter’s Formula• In metabolic acidosis the expected pCO2 can

be estimated from the HCO3

Expected pCO2 = (1.5 x HCO3) + 8 ± 2

• If the pCO2 is higher than predicted then there is an addition respiratory acidosis

• If the pCO2 is lower than predicted there is an additional respiratory alkalosis

– Expected pCO2 = (1.5 x HCO3) + 8 ±2

Predicting pCO2 in metabolic acidosis: Winter’s Formula

7.33 / 87 / 33 / 17 pH / pO2 / pCO2 / HCO3

– Expected pCO2 = (1.5 x HCO3) + 8 ±2– Expected pCO2 = 31-35


7.33 / 87 / 33 / 17 pH / pO2 / pCO2 / HCO3

– Expected pCO2 = (1.5 x HCO3) + 8 ±2– Expected pCO2 = 31-35– Actual pCO2 is 33, which is within the predicted range,

indicating a simple metabolic acidosis


7.33 / 87 / 33 / 17 pH / pO2 / pCO2 / HCO3




7.33 / 87 / 33 / 17 pH / pO2 / pCO2 / HCO3

Appropriately compensated metabolic acidosis

• Metabolic acidosis is further evaluated by determining the anion associated with the increased H+ cation


It is either chloride

Non-Anion GapMetabolic Acidosis




Or it is not chloride

Anion GapMetabolic Acidosis


• These can be differentiated by measuring the anion gap.



Or it is not chloride

Anion GapMetabolic Acidosis

Anion gap

=

• Anion gap = Na – (HCO3 + Cl)

• Normal is 12

Calculating the anion gap

• Anion gap = 139 – (17 + 115)• Anion gap = 7

139 115 3.1 17

16

1.0


• Normal is 12– Varies from lab to lab– Average anion gap in healthy controls is 6 ±3

• Improving chloride assays have resulted in increased chloride levels and a decreased normal anion gap.


• Anion gap = 139 – (17 + 115)• Anion gap = 7

– Varies from lab to lab– Average anion gap in healthy controls is 6 ±3

• Improving chloride assays have resulted in increased chloride levels and a decreased normal anion gap.

139 115 3.1 17

16

1.0

Appropriately compensated non-anion gap metabolic acidosis

NAGMA: Loss of bicarbonate

GI loss of HCO3

Diarrhea

Surgical drains

Fistulas

Ureterosigmoidostomy

Obstructed ureteroileostomy

Cholestyramine

Renal loss of HCO3

Renal tubular acidosis

Proximal

Distal

Hypoaldosteronism

Saline infusionsDilutional acidosis

HCl intoxication

Chloride gas intoxication

Early renal failure

NAGMA: Loss of bicarbonate

GI loss of HCO3

Diarrhea

Surgical drains

Fistulas


Obstructed ureteroileostomy

Cholestyramine

Renal loss of HCO3

Renal tubular acidosis

Proximal

Distal

Hypoaldosteronism

140 102 4.4 24135 100 5.0 35135 50 5.0 90135 50 5.0 90

Plasma

Bile

Pancreas

Small intestines

Large intestines

110 90 35 40

Urine pH=5.5 Serum pH=7.4

100 fold difference



100 fold difference

Ureterosigmoidostomy Ureteroileostomy


100 fold difference

Renal causes of non-anion gap

• Renal tubular acidosis is a failure of the kidney to reabsorb all of the filtered bicarbonate or synthesize new bicarbonate to keep up with metabolic demands.

• Daily acid load– Protein metabolism consumes bicarbonate

– This bicarbonate must be replaced

– Generally equal to 1 mmol/kg

Bicarbonate handling• Normally 144 mmol of

bicarbonate per hour are filtered at the glomerulus– 24 mmol/L x 100 mL/min x 60

min/hour

– Equivalent to 3 amps of bicarb per hour or a bicarb drip running 1 liter per hour

3456 mmol/day 50-100 mmol/day

Bicarbonate handling• Normally 144 mmol of

bicarbonate per hour are filtered at the glomerulus– 24 mmol/L x 100 mL/min x 60

min/hour

– Equivalent to 3 amps of bicarb per hour or a bicarb drip running 1 liter per hour

• The kidney must create 50-100 mmol per day of new bicarb-onate to replace bicarbonate lost buffering the daily acid load.

3456 mmol/day 50-100 mmol/day

Proximal tubule: reabsorption of filtered bicarbonate

Distal tubule, completion of reabsorption and replacing bicarbonate lost to the daily acid load.

Fate of excreted hydrogen ion

The minimal urine pH is 4.5. This is a H+ concentration a 1000 times that of plasma.



ButIt still is only 0.04 mmol/L



ButIt still is only 0.04 mmol/L

In order to excrete 50 mmol (to produce enough bicarb-onate to account for the daily acid load) one would need to produce 1250 liters of urine.


Ammonium

Titratable acid

Proximal RTA (Type 2)

• The Tm is the maximum plasma concentration of any solute at which the proximal tubule is able to completely reabsorb the solute.

• Beyond the Tm the substance will be incompletely reabsorbed and spill in the urine.

• In Proximal RTA the Tm for bicarbonate is reduced from 26 to 15-20 mmol/L.

Na+

H2OHCO3 Glucose

Amino Acids

• Proximal RTA– Tm for bicarbonate at 15

• Serum bicarbonate above the Tm


24 mmol/L

15 mmol/L

pH 8


• Serum bicarbonate at the Tm


15 mmol/L

15 mmol/L

pH 5


• Serum bicarbonate below the Tm


12 mmol/L

12 mmol/L

pH 5

Proximal RTA: etiologies

• Acquired– Acetylzolamide – Ifosfamide – Chronic hypocalcemia– Multiple myeloma– Cisplatin– Lead toxicity– Mercury poisoning– Streptozocin– Expired tetracycline

• Genetic– Cystinosis– Galactosemia– Hereditary fructose

intolerance– Wilson’s disease

• Hyperparathyroidism• Chronic hypocapnia

– Intracellular alkalosis

Proximal RTA: consequences

• Hypokalemia• Bone disease

– Bone buffering of the acidosis

– Decreased 1,25 OH D leading to hypocalcemia and 2° HPTH

• Not typically complicated by stones

Distal RTA (Type 1)

• A failure to secrete the daily acid load at the distal tubule is distal rta.

• A failure in any one of the three steps in urinary acidification can result in RTA

• Each step has been demonstrated to fail and has independent etiologies

Distal RTA: Voltage dependent

• Only variety of distal RTA which is hyperkalemic

• Differentiate from type 4 by failure to respond to fludrocortisone.– Obstructive uropathy– Sickle cell anemia– Lupus– Triameterene– Amiloride

Distal RTA: H+ Secretion

• Called classic distal RTA

• Most common cause of distal RTA– Congenital– Lithium– Multiple myeloma– Lupus– Pyelonephritis– Sickle cell anemia– Sjögren’s syndrome– Toluene (Glue sniffing)– Wilson’s disease

Distal RTA: Gradient defect

• Amphotercin B

Distal RTA: consequences

• Bones– Chronic metabolic

acidosis results in bone buffering.

• Bicarbonate• Phosphate • Calcium

• Kidney stones– Calcium phosphate

stones• Due to hypercalciuria• Increased urine pH• Decreased urinary

citrateWell Mr. Osborne, it may not be kidney stones after all.

Hypoaldosteronism

• Chronic hyperkalemia of any etiology decreases ammonia- genesis

• Without ammonia to convert to ammonium total acid excretion is modest

• Urinary acidification is intact

• Acidosis is typically mild without significant bone or stone disease

• Primary problem is with high potassium

non-anion gap metabolic acidosis

Diagnosing the cause of:

Ammonium

Titratable acid

To look for renal H+ clearance look for urinary ammonium

Ammonium

Titratable acid

To look for renal H+ clearance look for urinary ammonium

NH4+

Urinary anion gap: Urinary ammonium detector

(Na+ + K+) – Cl–

• In the presence of ammonium the chloride will be larger than the sum of Na and K.

• So a negative anion gap means ammonium in the urine.

• Ammonium in the urine means effective renal acid secretion

• Ammonium in the urine usually rules out RTA

NAGMA and urinary anion gap• Diarrhea


– Negative


– Negative• Proximal RTA

– At baseline

15 mmol/L

15 mmol/L

pH 5



– At baseline• Negative

15 mmol/L

15 mmol/L

pH 5




– During treatment

24 mmol/L

15 mmol/L

pH 8




– During treatment• Positive

24 mmol/L

15 mmol/L

pH 8





– During acid load

12 mmol/L

12 mmol/L

pH 5





– During acid load• Negative

12 mmol/L

12 mmol/L

pH 5






• Distal RTA






• Distal RTA:– Positive







• Type IV RTA







• Type IV RTA– Positive


139 115 3.1 17

16

1.0

7.34 / 87 / 33 / 16

U/A pH 6.5

80 115 45

Urine electrolytes


139 115 3.1 17

16

1.0

7.34 / 87 / 33 / 16

U/A pH 6.5

80 115 45

Urine electrolytes

Appropriately compensated non-anion gap metabolic acidosis due

to distal RTA

74 y.o. female with 34 year history of DM c/o weakness

139 123 6.6 17

21

1.2

7.34 / 87 / 33 / 16

Albumin 1.8






7.34 / 87 / 33 / 16pH / pO2 / pCO2 / HCO3






7.34 / 87 / 33 / 16pH / pO2 / pCO2 / HCO3


7.34 / 87 / 33 / 16pH / pO2 / pCO2 / HCO3






7.34 / 87 / 33 / 16pH / pO2 / pCO2 / HCO3


7.34 / 87 / 33 / 16pH / pO2 / pCO2 / HCO3




Metabolic Acidosis




7.33 / 87 / 33 / 17 pH / pO2 / pCO2 / HCO3




7.33 / 87 / 33 / 17 pH / pO2 / pCO2 / HCO3

Appropriately compensated metabolic acidosis



139 123 6.6 17

16

1.0



139 123 6.6 17

16

1.0• Anion gap = 139 – (123 + 17)• Anion gap = -1



139 123 6.6 17

16

1.0• Anion gap = 139 – (123 + 17)• Anion gap = -1A negative anion gap!That’s got to mean something!

Hypoalbuminuria, hypophosphatemia• The “other anions” includes phosphate and albumin

• Hypoalbuminuria and hypophosphatemia lowers the anion gap

• If one fails to adjust the upper and lower limit of the normal anion gap, altered albumin and phosphorous can hide a pathologic anion gap




Adjusted Normal Anion Gap


• To estimate the normal anion gap for any individual multiply the albumin by 2.5 and add half the phosphorous



Adjusted Normal Anion Gap

Other causes of a low anion gap• Increased chloride

– Hypertriglyceridemia– Bromide– Iodide

• Decreased “Unmeasured anions”– Albumin– Phosphorous– IgA

• Increased “Unmeasured cations”– Hyperkalemia– Hypercalcemia– Hypermagnesemia– Lithium– Increased cationic paraproteins

• IgG

Albumin

Phos

IgA

Chloride

Bicarb

Sodium

Potassium

Calcium

Magnesium

IgG

Normalanion

gap

Recent lab history

non-anion gap metabolic acidosis with hyperkalemia

Diagnose the cause of:



1. Type four RTA, hyporenin-hypoaldo




2. Hyperkalemic Distal (Type 1) RTA, voltage dependent distal RTA

A dipstick for aldosterone activity:The trans-tubular potassium gradientThe TTKG

Trans-tubular Potassium Gradient(TTKG)• The ratio of tubular to

venous K indicates the level of aldosterone activity.

• In the presence of hyperkalemia the ratio should be > 10.

• In the presence of hypokalemia the ratio of < 4.

• The trans-tubular potassium gradient adjusts the urine potassium for water loss in the collecting ducts.

• This allows the use of urinary potassium to calculate the ratio of potassium from the tubule to the interstitium in the CCD.

€

TTKG =KCCD

K plasma

KCCD =Kurine

OsmurineOsmplasma

TTKG =

Kurine

OsmurineOsmplasma

K plasma

TTKG =Kurine × OsmPlasma

K plasma × Osmurine

Trans-tubular Potassium Gradient(TTKG)

– Urine osmolality > serum osmolality

• Pre-requisites to using the TTKG as a measure of aldosterone activity:




Fluid leaving the LoH has an osmolality of 100 mOsm/Kg





In the presence of ADH water leaves the DCT so that the tubular fluid becomes isosmotic





In the presence of ADH water leaves the DCT so that the tubular fluid becomes isosmotic


– Urine Na > 20 mmol/L




Lets play low normal or high! TTKG and Aldo level





• Low TTKG• Low aldosterone






• Low TTKG• Low aldosterone


• Low TTKG• High aldosterone


4.7 5 5.2 5.4 5.76.6

3.8

1.8

-5

0

5

10

15

20

25

-5 -4 -3 -2 -1 0

BicarbonatePotassiumAlbuminAnion Gap


4.7 5 5.2 5.4 5.76.6

3.8

1.8

-5

0

5

10

15

20

25

-5 -4 -3 -2 -1 0

BicarbonatePotassiumAlbuminAnion Gap

Both the bicarbonate and potassiumwere normal at admission. This ishospital acquired RTA (type 1 or 4)



2. Hyperkalemic Distal (Type 1), voltage dependent distal RTA

Hospital acquired RTA really means drug induced RTA



Hospital acquired RTA really means drug induced RTALets play: Name that drug!





• Spironolactone• ACEi/ARB• Heparin

Lets play: Name that drug!





• Spironolactone• ACEi/ARB• Heparin


• Amiloride• Triamterene• Trimethoprim

Lets play: Name that drug!




Patient’s TTKG was 2.7 with a K of 5.7

Aldosterone was 22

The patient had been started on a high dose of TMP/SMX for a partially resistant urinary tract infection

Two women with non-anion

gap metabolic acidosis

One with hypokalemia

One with hyperkalemia

Both with distal RTA

non-anion gap metabolic acidosis (nagma)

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